Process for the preparation of 1-benzyl-3-hydroxymethyl-1h-indazole and its derivatives and required magnesium intermediates

ABSTRACT

The present invention relates to the process for the conversion of 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (II), to the 1-benzyl-3-hydroxylmethyl-1H-indazole according to formula (I).

SCOPE OF THE INVENTION

This invention relates to a process for the preparation of1-benzyl-3-hydroxymethyl-1H-indazole.

In particular, the present invention relates to the process for theconversion of 1-benzyl-3-hydroxymethyl-1H-indazole according to formula(II) below, to the 1-benzyl-3-hydroxymethyl-1H-indazole according toformula (I) below.

STATE OF THE ART

European patent EP-B-0 382 276 describes some1-benzyl-3-hydroxymethyl-1H-indazole derivatives of formula (A) havinganalgesic activity:

in which

R and R′, which may be the same or different, are H or C₁₋₅ alkyl, and

R″ is H or C₁₋₄ alkyl,

possibly in the form of its salt with a pharmaceutically-acceptableorganic or inorganic base when R″ is H.

In turn, European patent EP-B-0 510 748 on the other hand describes theuse of the same derivatives for the preparation of a pharmaceuticalcomposition active in the treatment of auto-immune diseases.

In addition to this, document EP-B1-0 858 337 describes a pharmaceuticalcomposition comprising a compound of formula (A) in which R═R′═CH₃ andR″═H, and an immunosuppressant.

European patent EP-B-1 005 332 describes the use of the same derivativesto prepare a pharmaceutical composition active in the treatment ofconditions deriving from the production of MCP-1.

Finally international patent application WO 2008/061671 describes theuse of a compound of formula (A) to reduce blood levels oftriglycerides, cholesterol and glucose.

Various processes for the preparation of compounds of formula (A) aredescribed in the abovementioned patent EP-B-0 382 276.

The processes described in patent EP-B-0 382 276 have as their key pointthe preparation of 1-benzyl-3-hydroxymethyl-1H-indazole, from which thecompounds of formula (A) can be obtained via three different reactionroutes.

The first reaction route provides for the conversion of1-benzyl-3-hydroxymethyl-1H-indazole into the corresponding alcoholatewhich is then caused to react with X—CRR′—COOR″, where X is a leavinggroup selected from the group comprising halogens, arylene-SO₂—O—, oralkylene-SO₂—O—, to yield the compounds of formula (A).

The second reaction route provides for the conversion of1-benzyl-3-hydroxymethyl-1H-indazole into the corresponding3-halogenomethyl derivative which is subsequently caused to react withan alcoholate of formula MeO—CRR′—COOR″, where Me is an alkali metal, toyield the compounds of formula (A).

The third reaction route provides for the reaction of1-benzyl-3-hydroxymethyl-1H-indazole with chloroform and a ketone offormula O═CRR′ in the presence of an alkaline base such as sodiumhydroxide to yield the compounds of formula (A) where R″ is hydrogen.

Preparation of the key intermediate 1-benzyl-3-hydroxymethyl-1H-indazoleby the processes described in patent EP-B-0 382 276 is carried out byreducing the corresponding 3-carboxylic acid with a suitable reducingagent, such as for example aluminium lithium hydride (LiAlH₄).

BRIEF DESCRIPTION OF THE INVENTION

The Applicant has become aware that the processes of synthesis known inthe art and described in the abovementioned patent EP-B-0 382 276 have anumber of disadvantages.

Firstly, 1-benzyl-1(H)-indazol-3-carboxylic acid is not a product whichcan be easily obtained on the market, and is rather expensive. Inparticular there are few suppliers and the synthesis routes described inthe literature provide for benzylation of the corresponding1(H)-indazol-3-carboxylic acid, which is also expensive and not easy toobtain. In the second place, reduction of the1-benzyl-1(H)-indazol-3-carboxylic acid to obtain1-benzyl-3-hydroxymethyl-1H-indazole proceeds with high dilutionfactors.

Furthermore the second reaction route provides for the use of thionylchloride to convert the 1-benzyl-3-hydroxymethyl-1H-indazole into thecorresponding 3-chloromethyl derivative. The use of thionyl chloride, ahighly toxic substance, gives rise to considerable safety and managementproblems in industrial processes.

Finally, the third reaction route (the Bargellini reaction) has shownindustrial disadvantages in low yields (less than 50%), the productionof carbon monoxide, a toxic and flammable gas, and the generation ofsignificant exothermic phenomena which are difficult to manageindustrially (Davis et al. Synthesis, 12, (2004), 1959-1962). Apart fromthis the Bargellini reaction finds better application in the synthesisof ethers from phenols and not from aliphatic alcohols (U.S. Pat. No.3,262,850; Cvetovich et al., J. Org. Chem., (2005), 70, 8560-8563).

The Applicant has therefore considered the problem of developing a newprocess for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole inorder to obtain compounds of formula (A) which is capable of overcomingthe abovementioned disadvantages. In particular the Applicant hasextended the problem to the preparation of1-benzyl-3-hydroxymethyl-1H-indazoles having the following formula (II).

in order to obtain compounds having the following formula (I)

in which the substituents from R₁ to R₁₂ have the meanings indicatedbelow in the detailed description and in the claims.

The Applicant has found a new process for the preparation of1-benzyl-3-hydroxymethyl-1H-indazoles of formula (II) to obtaincompounds of formula (I) which considerably improves on one handindustrial applicability, yields and the costs of the new process incomparison with the processes known hitherto, and on the other hand thequality of the compounds obtained using it.

The Applicant has surprisingly found that1-benzyl-3-hydroxymethyl-1H-indazole, or its derivatives of formula(II), can easily be obtained by reacting a Grignard reagent having theformula (IV) described below with a suitable electrophilic compound suchas, for example, aldehydes, ketones or amides, with subsequentreduction, if necessary, of the intermediate carbonyl compound.

In particular the Applicant has surprisingly found that the Grignardreagent of formula (IV) is easily obtained from1-benzyl-3-halogeno-1H-indazole or its derivatives of formula (III)described below through a halogen/magnesium exchange reaction withGrignard reagents of the alkyl magnesium halide type, at lowtemperature.

The Applicant also believes that the Grignard reagents of formula (IV)are not known in the art.

In fact the only indazole organometallic derivatives known in the art,with the metal in the 3 position, are those with metals such as zinc(Knochel et al., Synlett 2005, 267) or copper (Knochel et al., Synthesis2006, 15, 2618 and Knochel et al., Synlett 2004, 13, 2303-2306), whilereactions degrading the indazole ring in an attempt to prepare thecorresponding 3-organolithium compounds (Welch et al., Synthesis, 1992,937) and 3-organosodium derivatives (Tertov et al., ZhurnalOrganicheskoi Khimii 1970, 6; 2140) are known.

The said 1-benzyl-3-halogeno-1H-indazole derivatives of formula (III),which are widely known in the literature, can easily be obtained byhalogenation of 1H-indazole in the 3 position with subsequentbenzylation in the 1 position (Collot et al., Tetrahedron, 1999, 55,6917; Coller et al., Aust. J. Chem. 1974, 27, 2343).

The Applicant has also surprisingly found that1-benzyl-3-hydroxymethyl-1H-indazole, or its derivatives of formula(II), can be readily converted into the corresponding 3-halogenomethylderivatives by mere treatment with hydrohalogen acids, and then tocompounds of formula (I) by etherification with the appropriatehydroxycarboxylic acid or ester of formula (VI).

Alternatively the Applicant has also surprisingly found that1-benzyl-3-hydroxymethyl-1H-indazole, or its derivatives of formula(II), can easily be converted into compounds of formula (I) byetherification with the appropriate α-halogenocarboxylic acid or esterof formula (VII) described below.

Accordingly, this invention relates to a process for the preparation of1-benzyl-3-hydroxymethyl-1H-indazole derivatives represented by thefollowing formula (I):

in which the substituents from R₁ to R₁₂ have the meanings indicatedbelow in the detailed description and in the claims,

in which,

a) the 1-benzyl-3-hydroxymethyl-1H-indazole or a derivative thereofrepresented by the following formula (II):

is caused to react with the hydrohalogen acid of formula HX″, where X″is a halogen atom selected from the group consisting in chlorine,bromine and iodine, preferably chlorine, to form1-benzyl-3-halogenomethyl-1H-indazole or a derivative thereofrepresented by the following formula (V):

b) the 1-benzyl-3-halogenomethyl-1H-indazole or a derivative thereofrepresented by the abovementioned formula (V) is caused to react in thepresence of a strong base with a compound represented by the followingformula (VI):

to form the 1-benzyl-3-hydroxymethyl-1H-indazole derivatives representedby the abovementioned formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Advantageously, the process for the preparation of1-benzyl-3-hydroxymethyl-1H-indazole and its derivatives represented bythe following formula (II):

in which

R₁ and R₂, which may be the same or different, are hydrogen or an alkylgroup having from 1 to 6 carbon atoms,

R₃, R₄ and R₈, which may be the same or different, may be hydrogen, analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 3 carbon atoms, and a halogen atom,

R₅ may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, analkoxy group having from 1 to 3 carbon atoms, a halogen atom, ortogether with one of R₆ and R₇ may form a ring having 5 or 6 carbonatoms, and

R₆ and R₇, which may be the same or different, may be hydrogen, an alkylgroup having from 1 to 5 carbon atoms, or one of R₆ and R₇ together withR₅ may form a ring having 5 or 6 carbon atoms,

provides that

a) a 1-benzyl-3-halogeno-1H-indazole of formula (III):

in which X is a halogen atom selected from iodine and bromine,preferably iodine, and R₃—R₈ have the abovementioned meanings,

is caused to react with an alkyl magnesium halide of formula RMgX′ whereR is an alkyl group from 1 to 6 carbon atoms and X′ is a halogen atomselected from bromine and chlorine, preferably chlorine, to formintermediate compound (IV):

b) the said intermediate compound (IV) is caused to react with acarbonyl compound of formula R₁—CO—R₂, where R₁ and R₂ have theabovementioned meanings, to form a compound of formula (II), oralternatively to b)

b′) the said intermediate compound (IV) is caused to react with an amideof formula R′R″N—CO—R₁, where R′ and R″, which may be the same ordifferent, are an alkyl group having 1 to 3 carbon atoms and R₁ has theabovementioned meanings, to form an intermediate compound (VIII):

which is caused to react with a carbonyl group reducing agent to form acompound of formula (II).

Advantageously, stage a) is performed in the presence of a suitablesolvent, such as for example tetrahydrofuran, 2-methyl-tetrahydrofuran,diethyl ether, dioxane, t-butyl-methyl ether, dibutyl ether, xylene,toluene, dichloromethane, chloroform, n-hexane, n-heptane and theirmixtures and so on, preferably 2-methyl-tetrahydrofuran,tetrahydrofuran, toluene, xylene and their mixtures, and even morepreferably 2-methyl-tetrahydrofuran.

The alkyl magnesium halide of formula RMgX′ used in stage a) may bemethylMgCl, ethylMgCl, n-propylMgCl, i-propylMgCl, n-butylMgCl,i-butylMgCl, sec-butylMgCl, t-butylMgCl, n-pentylMgCl, n-hexylMgCl,allylMgCl, cyclohexylMgCl, methylMgBr, ethylMgBr, n-propylMgBr,i-propylMgBr, n-butylMgBr, i-butylMgBr, sec-butylMgBr, t-butylMgBr,n-pentylMgBr, n-hexylMgBr, allylMgBr, cyclohexylMgBr, and preferablyi-propylMgCl. These reagents may be obtained commercially or preparedaccording to methods extensively described in the literature (Silvermanet al., Handbook of Grignard reagents, Chapter 2, CRC Press).

Advantageously, the exchange reaction in stage a) may be catalysed bythe addition of lithium salts, for example LiCl, as described in theliterature (Knochel et al., Chem. Commun., 2005, 543).

Advantageously, stage a) is carried out at a temperature of between −30°C. and +30° C., preferably at a temperature of between −20° C. and −10°C.

Advantageously, stage a) is carried out using a molar ratio between thealkyl magnesium halide of formula RMgX′ and the1-benzyl-3-halogeno-1H-indazole of formula (III) of between 1 and 4,preferably between 1.5 and 4.

Advantageously, stage b) is carried out in the presence of a suitablesolvent, such as for example tetrahydrofuran, 2-methyl-tetrahydrofuran,diethyl ether, dioxane, t-butylmethyl ether, dibutyl ether, xylene,toluene, dichloromethane, chloroform, n-hexane, n-heptane and theirmixtures, and so on, preferably 2-methyl-tetrahydrofuran,tetrahydrofuran, toluene, xylene and their mixtures, but preferably2-methyl-tetrahydrofuran.

Advantageously, stage b) is carried out using a carbonyl compoundselected from the group of aldehydes, such as for example formaldehyde,acetaldehyde, propanal, butanal, pentanal, hexanal, and the like, andketones such as for example acetone, ethylmethyl ketone, isobutylmethylketone, and so on. Formaldehyde is preferably used, and in particularpolymers such as suitably depolymerised paraformaldehyde or trioxane areused as a source of formaldehyde.

Advantageously, stage b) is carried out using a molar ratio between the1-benzyl-3-halogeno-1H-indazole of formula (III) and the carbonylcompound of formula R₁—CO—R₂ of between 1 and 6.

Advantageously, stage b) is carried out at a temperature of between −30°C. and +30° C., preferably at a temperature of between −10° C. and 0° C.

Advantageously, stage b′) is carried out using an alkyl amide selectedfrom the group comprising N,N-dimethylformamide, N,N-diethylformamide,N,N-di-n-propylformamide, N,N-dimethylacetamide, N,N-diethylacetamide,N,N-di-n-propylacetamide, N,N-dimethylpropionamide,N,N-diethylpropionamide, N,N-di-n-propylpropionamide, preferablyN,N-dimethylformamide.

Advantageously, stage b′) is carried out at a temperature of between−30° C. and +30° C., preferably at a temperature of between −10° C. and0° C.

In particular, stage b′) is carried out using a molar ratio between the1-benzyl-3-halogeno-1H-indazole of formula (III) and the amide offormula R′R″N—CO—R₁ of between 1 and 4.

Advantageously, the carbonyl group reducing agent used in stage b′) isselected from the group comprising hydrides, such as for example NaBH₄,KBH₄, LiBH₄, Zn(BH₄)₂, Ca(BH₄)₂, NaAlH₄, LiAlH₄, Et₃SiH, Bu₃SnH,i-Bu₂AlH, 70% NaAlH₂(OCH₂CH₂OCH₃)₂ in toluene, and derivatives. Thecarbonyl group reducing agent is preferably 70% NaAlH₂(OCH₂CH₂OCH₃)₂ intoluene. Carbonyl group reducing agents are extensively reported in theliterature (described, for example, in Smith, March, March's AdvancedOrganic Chemistry, 5th ed., pages 1197-1205, John Wiley & Sons, Inc. andCarey, Sundberg, Advanced Organic Chemistry, 4th ed., pages 262-290).

Advantageously, the reduction in stage b′) is carried out in thepresence of a suitable solvent such as for example tetrahydrofuran,2-methyl-tetrahydrofuran, diethyl ether, dioxane, t-butylmethyl ether,dibutyl ether, xylene, toluene, dichloromethane, chloroform, n-hexane,n-heptane, methanol, ethanol, n-propanol, i-propanol, diglyme(bis-(2-methoxyethyl)ether), pyridine, dimethylsulphoxide (DMSO), aceticacid, their mixtures and so on, preferably toluene, xylene,tetrahydrofuran, 2-methyl-tetrahydrofuran and their mixtures.

Advantageously the reduction in stage b′) is carried out at atemperature of between 10° and 100° C., preferably at a temperature ofbetween 20° C. and 60° C.

In particular, reduction of the carbonyl group in stage b′) is carriedout using a number of equivalents of hydride of between 1 and 3,preferably 2.

Advantageously, the R₁—R₈ groups in formulae (II), (III), (IV) and(VIII) described above may have the following meanings.

Preferably, R₁ and R₂, which may be the same or different, arerepresented by a hydrogen atom, or an alkyl group having from 1 to 3carbon atoms.

Preferably, R₃, R₄ and R₈, which may be the same or different, may behydrogen, a methyl group, an ethyl group, a methoxy group, an ethoxygroup, a chlorine atom and a fluorine atom.

Advantageously, R₅ may be hydrogen, a methyl group, an ethyl group, amethoxy group, an ethoxy group, a chlorine atom and a fluorine atom, ortogether with one of R₆ and R₇ may form a ring having 6 carbon atoms.

Preferably, R₆ and R₇, which may be the same or different, may behydrogen, a methyl group, an ethyl group, or one of R₆ and R₇ togetherwith R₅ may form a ring having 6 carbon atoms.

The present invention relates to a process for the preparation of1-benzyl-3-hydroxymethyl-1H-indazole derivatives represented by thefollowing formula (I):

in which

R₁—R₈ have the meanings in formula (II) above,

R₁₀ and R₁₁, which may be the same or different, are hydrogen or analkyl group having from 1 to 5 carbon atoms, and

R₁₂ is hydrogen or an alkyl group having from 1 to 4 carbon atoms.

The process for preparation of the 1-benzyl-3-hydroxymethyl-1H-indazolederivatives shown in the abovementioned formula (I) according to theinvention provides that

a) the 1-benzyl-3-hydroxymethyl-1H-indazole or a derivative thereofrepresented by the following formula (II):

in which R₁—R₈ have the abovementioned meanings,

is caused to react with a hydrohalogen acid of formula HX″, where X″ isa halogen atom selected from the group consisting in chlorine, bromineand iodine, preferably chlorine, to form1-benzyl-3-halogenomethyl-1H-indazole or a derivative thereofrepresented by the following formula (V):

in which R₁—R₈ and X″ have the abovementioned meanings,

b) the 1-benzyl-3-halogenomethyl-1H-indazole or a derivative thereofrepresented by the abovementioned formula (V) are caused to react in thepresence of a strong base with a compound represented by the followingformula (VI):

in which R₁₀, R₁₁, which may be the same or different, and R₁₂ have theabovementioned meanings, to form the1-benzyl-3-hydroxymethyl-1H-indazole derivatives represented by theabove formula (I).

Preferably the abovementioned process for the preparation of the1-benzyl-3-hydroxymethyl-1H-indazole derivatives represented by formula(I) may comprise formation of the salt of the carboxyl group representedby −COOR₁₂ by treatment with a pharmaceutically acceptable organic orinorganic base. This treatment may be carried out directly on thecorresponding acid when R₁₂ is hydrogen, or following the reaction ofhydrolysing the ester when R₁₂ is an alkyl group from 1 to 4 carbonatoms.

Advantageously, stage a) is carried out in aqueous solution or inorganic solvent. The hydrohalogen acid of formula HX″ used isconcentrated or dilute hydrochloric acid, hydrobromic acid or hydroiodicacid, preferably hydrochloric acid in a concentration such as to have amolar ratio between the acid and the compound of formula (II) of between1 and 20, preferably between 1 and 5, and even more preferablyapproximately 3.

Advantageously, stage a) is carried out at a temperature of between 25°C. and 100° C., preferably at a temperature of between 60° C. and 90° C.

The organic solvent preferably used in stage a) is selected from thegroup comprising toluene, xylene, acetic acid, dioxane, dibutylether,2-methyl-tetrahydrofuran.

Advantageously, stage b) is carried out in aprotic solvents, such as forexample tetrahydrofuran, dioxane, N,N-dimethylformamide, toluene,N-methylpyrrolidone, dimethylsulphoxide, hexamethylphosphoramide,acetone, isobutylmethyl ketone, methylethyl ketone or their mixtures,preferably toluene or N,N-dimethylformamide and their mixtures.

The strong base used in stage b) is preferably selected from the groupcomprising sodium hydride, metallic sodium, metallic potassium, butyllithium, lithium-diisopropyl amide, sodium amide, potassium hydride,preferably sodium hydride.

Advantageously, stage b) is carried out using an α-hydroxy acid selectedfrom the group comprising hydroxyacetic acid, lactic acid,α-hydroxyisobutyric acid, α-hydroxybutyric acid,2-ethyl-2-hydroxybutyric acid, 2-hydroxyisovaleric acid,2-hydroxy-3,3-dimethylbutyric acid, 2-hydroxyisocaproic acid, preferablyα-hydroxyisobutyric acid.

Advantageously, stage b) is carried out using an α-hydroxyester selectedfrom the group comprising methyl glycolate, ethyl glycolate, butylglycolate, methyl lactate, ethyl lactate, butyl lactate, t-butyllactate, isopropyl lactate, isobutyl lactate,methyl-2-hydroxyisobutyrate, ethyl-2-hydroxyisobutyrate,ethyl-2-hydroxyvalerate, t-butyl-2-hydroxybutyrate, preferablyethyl-2-hydroxyisobutyrate.

Preferably, the molar ratio between the1-benzyl-3-halomethyl-1H-indazole of formula (V) and the α-hydroxy acidor ester of formula (VI) is between 1 and 2, preferably approximately1.2.

In particular, the molar ratio between the α-hydroxy acid of formula(VI) and the strong base is between 1 and 3, preferably approximately 2.Similarly the molar ratio between the α-hydroxy ester of formula (VI)and the strong base is between 1 and 1.5, preferably approximately 1.

Advantageously, the groups R₁—R₁₂ in formulae (I), (II), (V), (VI) and(VII) described above may have the following meanings.

Preferably R₁ and R₂, which may be the same or different, arerepresented by a hydrogen atom, or an alkyl group having from 1 to 3carbon atoms.

Preferably, R₃, R₄ and R₈, which may be the same or different, may behydrogen, a methyl group, an ethyl group, a methoxy group, an ethoxygroup, a chlorine atom and a fluorine atom.

Advantageously, R₅ may be hydrogen, a methyl group, an ethyl group, amethoxy group, an ethoxy group, a chlorine atom and a fluorine atom, ortogether with one of R₆ and R₇ may form a ring having 6 carbon atoms.

Preferably, R₆ and R₇, which may be the same or different, may behydrogen, a methyl group, an ethyl group, or one of R₆ and R₇ togetherwith R₅ may form a ring having 6 carbon atoms.

Preferably, R₁₀ and R₁₁, which may be the same or different, arehydrogen or an alkyl group having 1 to 3 carbon atoms, and R₁₂ ishydrogen or an alkyl group having 1 to 3 carbon atoms.

The following examples are intended to illustrate this invention withouthowever restricting it in any way.

EXPERIMENTAL PART

The compounds 3-iodo-1H-indazole and 1-benzyl-3-iodo-1H-indazole wereprepared according to the procedure reported by Collot et al.(Tetrahedron, 55, 6917, 1999). The compound 3-bromo-1H-indazole wasprepared using the procedure reported by Coller et al. (Aust. J. Chem.1974, 27, 2343).

Example 1 Preparation of 1-benzyl-3-bromoindazole

3-bromo-1H-indazole (90.4 g, 0.459 mol, 1.0 eq.) and toluene (450 mL)were placed in a 1 litre flask fitted with a mechanical stirrer under anatmosphere of nitrogen. Then potassium t-butoxide (t-BuOK, 54.2 g, 0.483mol, 1.05 eq.) was added at room temperature over about half an hour andbenzyl bromide (86.3 g, 0.505 mol, 1.1 eq.) was added over approximately1.5 hours. The mixture was left stirred at the same temperature untilthe reaction was complete (checked by TLC, approximately 3 hours). Then0.1 M HCl (45 mL) and water (90 mL) were added and the resulting phaseswere separated. The organic phase was washed with water, and the solventwas evaporated off at reduced pressure in order to obtain a red oilyresidue. The product was then precipitated through the addition ofn-heptane, filtered and dried under vacuum at room temperature. Yield:65.9 g of beige solid (yield 50%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 5.67 (s, 2H), 7.29 (m, 6H), 7.50 (ddd,1H, J=8.6 Hz, 6.9 Hz, 1.0 Hz), 7.60 (dd, 1H, J=8.2 Hz, 0.7 Hz), 7.80(dd, 1H, J=8.6 Hz, 0.7 Hz).

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 52.2, 110.4, 119.5, 121.7, 122.9,127.4, 127.4, 127.6, 127.7, 128.6, 128.6, 129.6, 136.9, 140.5.

Example 2 Preparation of 1-benzyl-3-hydroxymethyl-1H-indazole

A solution of i-propylmagnesium chloride (i-PrMgCl) in2-methyltetrahydrofuran (Me-THF) was prepared in a suitably thoroughlydried flask maintained under an atmosphere of nitrogen from magnesiummetal (Mg, 10.91 g, 0.4489 mol, 1.5 eq.) activated with iodine crystalsand a solution of isopropyl chloride (i-PrCl, 41.0 mL, 0.4489 mol, 1.5eq.) in anhydrous Me-THF (185 mL). After cooling to approximately −10°C. a solution of 1-benzyl-3-iodo-1H-indazole (100 g, 0.2993 mol, 1.0eq.) in anhydrous Me-THF (120 mL) was added over 1 hour keeping thetemperature constant. The reaction mixture was kept stirred for afurther hour to complete the halogen/magnesium exchange, and a yellowsuspension was obtained. Gaseous formaldehyde (generated by heating asuspension of 54 g of paraformaldehyde in 150 mL of xylene atapproximately 115° C.) was passed over this for approximately two hoursat a temperature of below 0° C. When the reaction was complete, diluteH₃PO₄ was added and the excess of re-polymerised paraformaldehyde wasremoved by filtration. The phases were separated and the organic phasewas then washed with a dilute solution of NaHCO₃ and then concentrated.The product, precipitated out by the addition of n-hexane, was collectedby filtration and dried. Yield: 56.8 g of white solid (79.6%).

mp: 85-86° C.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 4.79 (d, 2H, J=5.8 Hz), 5.27 (t, 1H,J=5.8 Hz), 5.6 (s, 2H), 7.12 (t, 1H, J=7.5 Hz), 7.28 (m, 5H), 7.36 (t,1H, J=7.2 Hz), 7.64 (d, 1H, J=8.5 Hz), 7.86 (d, 1H, J=8.2 Hz).

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 51.6, 56.6, 109.6, 120.0, 120.9,122.2, 126.2, 127.3, 127.3, 127.4, 128.5, 128.5, 137.7, 140.3, 145.2.

Example 3 Preparation of 1-benzyl-3-hydroxymethyl-1H-indazole

A solution of 2M i-PrMgCl in THF (69 mL, 138 mmol, 4.0 eq.) was added toa suitably thoroughly dried flask maintained under a nitrogenatmosphere. The solution was cooled to approximately −10° C. A solutionof 1-benzyl-3-bromo-1H-indazole (10 g, 34.8 mmol, 1.0 eq.) in anhydrousTHF (40 mL) was added over approximately one hour keeping thetemperature constant. The reaction mixture was kept stirred for at least6 hours, and a yellow suspension was obtained. Gaseous formaldehyde(generated by heating a suspension of 16.7 g of paraformaldehyde in 60mL of xylene at approximately 115° C.) was passed over this forapproximately two hours at a temperature of below 0° C. When thereaction was complete, dilute H₃PO₄ was added and the excess ofre-polymerised paraformaldehyde was removed by filtration. Me-THF (60mL) was added to the mixture and the phases were separated. The organicphase was washed with a dilute solution of NaHCO₃. After concentrationof the organic phase an oily residue containing the product wasobtained. Subsequent purification of the crude product by silica gelchromatography yielded 2.8 g of white solid (yield: 34%).

mp: 85-86° C.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 4.79 (d, 2H, J=5.8 Hz), 5.27 (t, 1H,J=5.8 Hz), 5.6 (s, 2H), 7.12 (t, 1H, J=7.5 Hz), 7.28 (m, 5H), 7.36 (t,1H, J=7.2 Hz), 7.64 (d, 1H, J=8.5 Hz), 7.86 (d, 1H, J=8.2 Hz).

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 51.6, 56.6, 109.6, 120.0, 120.9,122.2, 126.2, 127.3, 127.3, 127.4, 128.5, 128.5, 137.7, 140.3, 145.2.

Example 4 Preparation of 1-benzyl-3-chloromethyl-1H-indazole

1-benzyl-3-hydroxymethyl-1H-indazole (400 g, 1.7 mol, 1 eq.), toluene(1.6 L) and concentrated HCl (422 mL, 5.1 mol, 3.0 eq.) were added to athree-necked flask fitted with a mechanical stirrer and refluxcondenser.

The reaction mixture was heated to approximately 90° C. and kept stirreduntil the reaction was complete (checked by TLC, approximately twohours). After cooling to room temperature NaCl was added (approximately10 g), the phases were separated, and the aqueous phase was discharged.The organic phase was washed with a saturated solution of NaHCO₃(approximately 100 mL) and then concentrated. The product, precipitatedout by the addition of n-hexane (approximately 500 mL), was filtered anddried. Yield: 398.2 g of white solid (91%).

mp: 89-91° C.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 5.14 (s, 2H), 5.65 (s, 2H), 7.27 (m,6H), 7.43 (m, 1H), 7.12 (d, 1H, J=8.5 Hz), 7.88 (d, 1H, J=8.2 Hz)

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 38.2, 51.8, 110.2, 120.1, 120.9,121.7, 126.7, 127.3, 127.3, 127.5, 128.5, 128.5, 137.2, 140.4, 140.6.

Example 5 Preparation of2-[1(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid

Ethyl-2-hydroxyisobutyrate (18.5 g, 140 mmol, 1.2 eq.), toluene (100 mL)and DMF (20 mL) were placed in a three-necked flask fitted with amechanical stirrer and a reflux condenser under an inert atmosphere. Adispersion of 60% NaH (5.6 g, 140 mmol, 1.2 eq.) was added to themixture in portions over a period of approximately 1.5 hours. A solutionof 1-benzyl-3-chloromethyl-1H-indazole (30 g, 117 mmol, 1 eq.) intoluene (90 mL) and DMF (60 mL) was then added dropwise. The reactionmixture was heated to approximately 90° C. and kept at that temperatureuntil the reaction was complete (checked by TLC, approximately 10hours). After cooling to room temperature the mixture was washed withacidified water and water. The organic phase was concentrated underreduced pressure and the oily residue obtained was treated with 10 MNaOH (36 mL) at reflux temperature for at least 3 hours. The product,which was precipitated out by the addition of concentrated HCl, wasfiltered and dried. Yield: 32.3 g of white solid (85%).

mp: 133-134° C.

Elemental analysis:

Calculated: C, (70.35); H, (6.21); N, (8.64), Found: C, (70.15); H,(6.17); N, (8.63).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 1.44 (s, 6H), 4.76 (s, 2H), 5.60 (s,2H), 7.14 (t, 1H, J=7.6 Hz), 7.20-7.34 (m, 5H), 7.37 (ddd, 1H, J=8.3 Hz,7.0 Hz, 1.1 Hz), 7.66 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=8.1 Hz), 12.77(s, 1H).

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 24.48, 24.48, 51.63, 59.65, 76.93,109.69, 120.22, 121.06, 122.62, 126.28, 127.36, 127.36, 127.44, 128.46,128.46, 137.49, 140.31, 141.97, 175.46.

Example 6 Preparation of 1-benzyl-1H-indazol-3-carbaldehyde

A solution of i-PrMgCl in THF was prepared in a suitably thoroughlydried flask maintained under a nitrogen atmosphere from magnesium metal(Mg, 164 mg, 6.75 mmol, 1.5 eq.) activated with iodine crystals and asolution of i-PrCl (0.62 mL, 6.75 mmol, 1.5 eq.) in anhydrous THF (2.8mL).

After cooling to approximately −10° C. a solution of1-benzyl-3-iodo-1H-indazole (1.5 g, 4.5 mmol, 1.0 eq.) in anhydrous THF(5 mL) was added to the reaction mixture over one hour keeping thetemperature constant. The reaction mixture was kept stirred for afurther hour to complete the halogen/magnesium exchange, yielding ayellow suspension. While stirring, dimethylformamide (DMF) (1.4 mL, 18mmol, 4 eq.) was added to the suspension over one hour at a temperaturebelow 0° C. and the reaction mixture was kept stirred at the sametemperature until the reaction was complete (checked by TLC).

Dilute H₃PO₄ and toluene were added to the reaction mixture and thephases were separated. The organic phase was washed with a solution ofdilute NaHCO₃. After the organic phase had been concentrated, theproduct, precipitated out by the addition of n-hexane, was filtered anddried. Yield: 1.0 g of yellowish solid (94%).

hu 1H NMR (300 MHz, DMSO-d₆) δ (ppm) 5.84 (s, 2H), 7.32 (m, 5H), 7.39(ddd, 1H, J=8.1 Hz, 7.0 Hz, 1.0 Hz), 7.53 (ddd, 1H, J=8.4 Hz, 7.0 Hz,1.2 Hz) 7.90 (dt, 1H, J=8.5 Hz, 1.0 Hz), 8.16 (dt, 1H, J=8.1 Hz, 1.2Hz), 10.19 (s, 1H).

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 52.9, 111.0, 121.0, 121.2, 124.2,127.5, 127.6, 127.6, 127.9, 128.6, 128.6, 136.2, 140.7, 142.4, 186.8.

Example 7 Preparation of 1-benzyl-3-hydroxymethyl-1H-indazole

1-benzyl-1H-indazol-3-carbaldehyde (2.36 g, 10 mmol, 1 eq.) and toluene(12 mL) were placed in a thoroughly dried 100 mL flask fitted with amagnetic stirrer and inerted with nitrogen. A 70% solution of sodiumdihydro-bis(2-methoxyethoxy)aluminate in toluene (2.8 mL, 10 mmol, 2eq.) was then slowly added to the solution at room temperature. Once thereaction was complete (after approximately 15 minutes), 2 M HCl (10 mL),H₂O (10 mL) and toluene (15 mL) were added. The phases were separatedand the aqueous phase was extracted twice with toluene. The pooledorganic phases were washed with water and concentrated. The product wasthen precipitated out by adding n-hexane, filtered and dried. Yield:1.95 g of white solid (82.0%).

mp: 85-86° C.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 4.79 (d, 2H, J=5.8 Hz), 5.27 (t, 1H,J=5.8 Hz), 5.6 (s, 2H), 7.12 (t, 1H, J=7.5 Hz), 7.28 (m, 5H) 7.36 (t,1H, J=7.2 Hz), 7.64 (d, 1H, J=8.5 Hz), 7.86 (d, 1H, J=8.2 Hz).

¹³C NMR (300 MHz, DMSO-d₆) δ (ppm) 51.6, 56.6, 109.6, 120.0, 120.9,122.2, 126.2, 127.3, 127.3, 127.4, 128.5, 128.5, 137.7, 140.3, 145.2.

1. A process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazolerepresented by the following formula (I):

in which R₁ and R₂, which may be the same or different, are hydrogen oran alkyl group having 1 to 6 carbon atoms, R₃, R₄ and R₈, which may bethe same or different, may be hydrogen, an alkyl group having 1 to 5carbon atoms, an alkoxy group having 1 to 3 carbon atoms and a halogenatom, R₅ may be hydrogen, an alkyl group having 1 to 5 carbon atoms, analkoxy group having 1 to 3 carbon atoms, a halogen atom, or togetherwith one of R₆ and R₇ may form a ring having 5 or 6 carbon atoms, R₆ andR₇, which may be the same or different, may be hydrogen, an alkyl grouphaving 1 to 5 carbon atoms, or one of R₆ and R₇ together with R₅ mayform a ring having 5 or 6 carbon atoms, R₁₀ and R₁₁, which may be thesame or different, are hydrogen or an alkyl group having 1 to 5 carbonatoms, and R₁₂ is hydrogen or an alkyl group having 1 to 4 carbon atoms,in which a) 1-benzyl-3-hydroxymethyl-1H-indazole or a derivative thereofrepresented by the following formula (II):

is caused to react with a hydrohalogen acid of formula HX″, where X″ isa halogen atom selected from the group comprising chlorine, bromine andiodine, preferably chlorine, to form1-benzyl-3-halogenomethyl-1H-indazole or a derivative thereofrepresented by the following formula (V):

b) 1-benzyl-3-halogenomethyl-1H-indazole or a derivative thereofrepresented by the abovementioned formula (V) is caused to react in thepresence of a strong base with a compound represented by the followingformula (VI):

to form the 1-benzyl-3-hydroxymethyl-1H-indazole represented by theabovementioned formula (I).
 2. The process of preparation according toclaim 1, in which the said 1-benzyl-3-hydroxymethyl-1H-indazolerepresented by formula (I) are caused to form salts with the carboxylgroup —COOR₁₂ by treatment with a pharmaceutically acceptable organic orinorganic base.
 3. The process of preparation according to claim 1wherein R₁ and R₂, which may be the same or different, are representedby a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms.
 4. Theprocess of preparation according to claim 1 wherein R₃, R₄ and R₈, whichmay be the same or different, may be hydrogen, a methyl group, an ethylgroup, a methoxy group, an ethoxy group, a chlorine atom and a fluorineatom,
 5. The process of preparation according to claim 1 wherein R₅ maybe hydrogen, a methyl group, an ethyl group, a methoxy group, an ethoxygroup, a chlorine atom and a fluorine atom, or together with R₆ and R₇may form a ring having 6 carbon atoms, and
 6. The process of preparationaccording to claim 1 wherein R₆ and R₇, which may be the same ordifferent, may be hydrogen, a methyl group, an ethyl group, or one of R₆and R₇ together with R₅ may form a ring having 6 carbon atoms.